P754: INITIAL RESULTS OF PHASE I/II STUDY OF AZACITIDINE IN COMBINATION WITH QUIZARTINIB FOR PATIENTS WITH MYELODYSPLASTIC SYNDROME AND MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM WITH FLT3 OR CBL MUTATION
Authors: T. Abuasab, E. Jabbour, N. Short, M. Konopleva, K. S. Chien, S. Fareed Mohamed, N. Daver, R. Kanagal-shamanna, G. Garcia-Manero, G. Montalban-Bravo
Journal: HemaSphere (2022)

Background: FMS-like tyrosine kinase 3 (FLT3) mutations occur in about 1% of patients (pts) with newly diagnosed myelodysplastic syndrome (MDS) and up to 19% at time of failure of hypomethylating agent (HMA). In addition, Casitas B-lineage Lymphoma mutations (CBL) are observed in 10% of pts with MDS/MPN and up to 13-15% of pts with CMML (mainly proliferative type). Preclinical studies suggest that CBL-mutant cells are dependent on FLT3 signaling. Aims: The primary objective is to determine the safety, tolerability, and maximum tolerable dose (MTD) of quizartinib. Secondary objectives include evaluation of overall response per IWG 2006 criteria, in addition to overall survival (OS), duration of response, leukemia-free survival (LFS), relapse-free survival (RFS). Methods: We designed a phase I/II study of azacitidine in combination with quizartinib for pts with newly diagnosed or previously treated MDS or MDS/MPN with detectable FLT3 and/or CBL mutations. The study included an initial phase I dose escalation portion followed by a phase II dose expansion. Dose escalation was planned to evaluate 3 dose levels of quizartinib (30, 40 and 60mg, respectively) administered on days 1-28 of every cycle in combination with azacitidine (75 mg/m2/day) on days 1-5 each 28-day cycle. Results: As of February 25, 2022, a total of 10 pts have been enrolled (9 in dose escalation, 1 in dose expansion): 7 pts with CMML, two with MDS with excess blast and one with atypical chronic myeloid leukemia (aCML). A total of 8 pts (80%) had normal karyotype, one ptn (10%) had complex karyotype and one (10%) had monosomy 7. Six pts had FLT3 mutations and 4 pts CBL mutations. Pts characteristics are summarized in Table 1. Nine out of 10 pts were evaluable at the time of the analysis. Median number of cycles administered was 5 (range 2-10). All pts have achieved response so far with 8 pts (89%) having achieved marrow CR (mCR), including hematological improvement (HI) in 1 patient out of 3 pts with baseline cytopenias evaluable for HI. One patient had hematologic improvement-erythropoietic (HI-E) with control of leukocytosis and thrombocytosis to normal levels. During cycle 1, responses were associated with recovery of platelets to above 50 and 100x109/L by day 28 of therapy in 67% and 56% of pts, respectively. In addition, absolute neutrophils count (ANC) was recovered to 1 x109/L by day 28 in all pts except of one patient at day 52. With a median follow up of 9.87 months (range 2.5-18), the median response duration is 6.3 months (range 1.6-14.3) with a median OS of 17.34 months (range 2.5 – 18). A total of 4 pts (44%) have stopped the treatment: 1 patient due to disease relapse and one due to disease progression after both received 6 cycles of treatment and two proceeded to allogenic stem cell transplantation after achieving response. No dose-limiting toxicities have been observed to date up to the maximum dose of 60 mg of quizartinib. Two pts required dose reductions of Quizartinib, one due to cytopenias and the other one due to concomitant posaconazole administration. Regarding the grade 3 or more adverse events (AEs): 3 pts (33%) had severe anemia/thrombocytopenia, 2 pts (22%) had skin infection, one patient (11%) had cardiac arrythmia with Mobitz II AV block and one patient (11%). Image:Summary/Conclusion: Preliminary data suggest azacitidine in combination with quizartinib for pts with MDS and MDS/MPN with FLT3 or CBL mutations have an acceptable toxicity profile and associated with promising responses. Further follow-up with a larger patient cohort are required to emphasize the safety and efficacy.